Harold C. Simmons Cancer Center Chemistry and Cancer Scientific Program Project Summary/Abstract The Chemistry and Cancer (CC) Program combines the expertise of synthetic and medicinal chemists, molecular biologists, biochemists, structural biologists, and clinician scientists to discover, design, and optimize drug-like small molecules that regulate biological pathways deregulated in cancer. There are a total of 16 members who are drawn from 4 departments on campus. CC's discovery process takes a two-pronged approach, starting from a chemistry-to-biology or a biology-to-chemistry direction. For the chemistry-to-biology approach, the discovery process starts with identifying natural or unnatural small molecules that are selectively cytotoxic to human cancer cell lines, followed by a rigorous target identification program. During this ?discovery biology? phase, chemists design specific derivatives to aid in biochemical pull-down and cross-linking studies. Or, if specific drug-resistant clones against the small molecule of interest can be generated, genetic and molecular biological studies can provide additional approaches to identify target pathways and/or drug resistance mechanisms. This unbiased approach is expected to identify novel cancer-specific pathways that can be chemically interrogated/regulated for proof-of-concept, early drug-discovery efforts. In the biology-to- chemistry approach, hypotheses regarding the ?drugability? and cancer relevance of specific biological pathways investigated by Simmons Cancer Center scientists can be tested with small-molecule agonists or antagonists. The CC Scientific Program will continue broadly with the following themes: Theme 1. Identifying the molecular targets of cancer cell?specific small-molecule toxins; Theme 2. Biochemical dissection of novel, cancer cell?specific pathways; Theme 3. Proof-of-concept preclinical development of cancer cell?specific small-molecule toxins; and Theme 4. Dissection, regulation, and targeting of the hypoxia response pathway. Current peer-reviewed funding for the CC Program is highlighted by $1.5 million from the NCI and $2.8 million from Cancer Prevention and Research Institute of Texas for total peer-reviewed funding of $7.1 million. CC Program members have authored 103 peer-reviewed publications since 2009, of which 19% were intra- programmatic and 30% inter-programmatic, and 15% of them inter-institutional with investigators from other NCI-designated cancer centers.